Malignant neoplasms accounted for approximately 7.6 million deaths worldwide in 2008, and as the population ages, that number projects to 13.2 million by 2030. Patient responses to specific drugs vary widely and it is unreasonable to expect current drug therapies to combat the expected increase in cancer deaths. Personalized medicine through the use of individualized biomarkers provides a potential means of combating this problem. The biomarkers, proteins expressed by the specific cancer cell, even to the patient's particular cancer, are exploited to detect and deliver chemotherapeutics. Polyclonal and monoclonal antibodies perform this task rather well, but drawbacks exist due to the complexity and expense of antibody production in addition to the difficulty of conjugating the antibodies to active cytotoxic agents. Even if individual biomarkers can be exploited to deliver chemotherapeutic agents to the cancer cell, multiple drugs must be engineered to kill the many different varieties and patient-specific cancers.
A potential approach is to exploit cancer-specific biomarkers to deliver a drug that is highly cytotoxic to all cells in all patients. Thus, only one highly cytotoxic drug must be synthesized, as long as it is specifically delivered to the cancer cell and then excreted. Cell-specific aptamers with a high affinity for leukemia, liver, lymphoma, colon, and most recently breast cancer, are known. Aptamers are very attractive drug delivery agents because they have low molecular weights, are formed by a relatively easy and reproducible DNA synthesis, display high binding affinities and molecular specificities, are easy modified, have fast tissue penetration, have low toxicity, are tunable in binding affinity, and are easy stored. Presently a number of diagnostic kits and imaging reagents using aptamers are in production.
No single cytotoxic drug has been identified, although many metal ions are highly cytotoxic to cancer. Hence, a metal ion is an obvious choice for an all-inclusive drug candidate. Moreover, since 1935 gold complexes have served as effective aurotherapeutic agents. Auranofin, used to treat rheumatoid arthritis, is also highly active against cervical carcinoma (HeLa) cells in vitro and effective against cis-platin resistant cancer cells. Numerous derivatives of gold complexes demonstrate high activity. However, as with most heavy metals including cis-platin, accumulation in the body causes significant negative side effects. One mode of accumulation is metal ion complex degradation, whereby a metal-aqua complex is formed and is difficult to excrete. Auranofin contains an Au—P(CH2CH3)3 gold bonded ligand, which has low stability. As a result, Auranofin accumulates in the body, which is detrimental. In contrast, N-heterocyclic carbene gold (NHCAu) complexes have the remarkable stability engendered by the Au-carbon bond. NHCAu complexes are stable towards water, acidic solutions, and heat—important qualities for a good drug candidate.
NHCAu complexes have a significant advantage because aquation and deposition of Au ions in the body can be minimized. Because NHC ligands are highly modular, the rapid and easy modification of steric and electronic properties of the metal complexes can fine-tune to the complex's cytotoxicity. Examples of NHCAu complexes that show activity are those in FIG. 1, which exhibit IC50 values as low as 0.21 μM for breast carcinoma (MDA MB231). For example, the chiral di-gold complex 5 of FIG. 1 exhibits activity towards cervical carcinoma (HeLa) with an IC50=8.7 μM. Unfortunately, the NHCAu complexes are also toxic to normal healthy cells, as in the case of 5 where an IC50=4.6 μM for healthy embryonic kidney cells (HEK) is observed.
Currently, cancer-specific aptamer-NHCAu conjugates or other aptamer-N-heterocyclic carbene metal (NHCM) conjugates are unknown but they have the potential to avoid toxicity to normal cells, while still being highly effective for the destruction of cancer cells. Thus, to prevent heavy metal accumulation in the patient and the undesired side effects, aptamer-NHCM conjugates where the gold or alternative metal ion remains attached to the aptamer are desirable.